This is a renewal application to continue our studies of synthetic peptide analogs of the amphipathic helix as a means of defining the relationship of amino acid sequence to lipid association for the exchangeable plasma apolipoproteins. The amphipathic helix hypothesis defines a general structural accomodation of amino acid residues resulting in Alpha-helical domains containing opposing polar and nonpolar faces; these helical regions are postulated to represent the lipid associating domains of apolipoproteins such as apolipoprotein A-I from HDL. The amphipathic helix is assumed to associate with a phospholipid phase by half burying itself at the interface between the polar headgroups and the fatty acyl chains, with its nonpolar face toward the lipid phase and its polar face toward the aqueous phase. In previously published work, we have demonstrated that the charge position is critical for lipid association. In order to further define the role of molecular topography of the amphipathic helix during lipid association, we intend to continue our synthesis of analog peptides varying in position and number of charged residues, in the hydrophobicity of the nonpolar "face", in the length of the "helix" and in the coplanarity of the entire "helical" polar-nonpolar interface. Studies of lipid specificity for peptide-phospholipid association are also planned. In an interesting development, recent studies in our laboratory have demonstrated that synthetic amphipathic peptides can displace apolipoproteins A-I and C-III from native HDL and VLDL, respectively. We plan to continue these studies, as well as studies of the structure of peptide-phospholipid complexes. As part of our overall plan we will develop means to quantitate affinity of amphipathic peptides for phospholipid. As a long term goal, we intend to study the effect of the amphipathic helix on LCAT and lipoprotein lipase activity in the plasma lipoproteins.